Calcium channels (Ca channels) are membrane proteins that transmit information into cells by controlling influx of Ca2+ into the cells. In particular, voltage-dependent Ca channels present in excitatory cells such as nerve cells and muscle cells are proteins that play an important role of converting information transmitted through changes in membrane potential, into intracellular information which is an increase in Ca2+ concentration.
Various voltage-dependent Ca channels have been identified from nerve cells and muscle cells (Bean, B. P. et al, Ann. Rev. Physiol., 51, pp. 367–384, 1989; Ross P., Ann. Rev. Neurosci., 56, p. 337, 1990), and these are classified into six types (L, N, P, Q, R and T) according to their electrophysiological properties and susceptibility to antagonists.
Among these Ca channels, N-type Ca channel is a Ca channel characterized in that Ca2+ influx is inhibited by a peptide toxin isolated from cone shell, ω-conotoxin GVIA.
Calcium antagonists are widely used as antianginal drugs, antiarrhythmic drugs and therapeutic agents for hypertension, and their action mechanism is based on relaxation of vascular smooth muscles or suppression of myocardial contraction by inhibition of the Ca2+ influx into a cell through a specific binding to the L-type Ca channel present in a cell membrane. Meanwhile, it is being revealed that Ca2+ is an important factor for normal functions in nerves, such as release of nerve transmitter substances, formation of impulse patterns and outgrowth of neurites, while a Ca2+ kinetics change is deeply involved in diseases such as delayed nerve cell death after cerebral ischemia and a certain kind of epilepsy (Siesjo, Mayo Clin Proc., 61, p. 299, 1986). Over the last few years, existence of P-, N-, Q- and R-type Ca channels, which are specifically present in nerves, were confirmed in addition to L-type and T-type. Roles of these Ca channels in nervous functions draw attentions, and novel calcium antagonists targeting them are being actively developed at the same time.
In particular, it has been reported that the N-type Ca channel is expressed at nerve endings of the autonomic nervous system, and its role in control through autonomic nerves is attracting attentions (Lane D. H. et al., Science, 239, pp. 57–61, 1988; Diane L, et al., Nature, 340, pp. 639–642, 1989).
Functions of the N-type Ca channel have hitherto been evaluated by conducting 1) an in vitro experiment using synaptosomes or cultured nerve cells or 2) an in vivo experiment using administration of ω-conotoxin GVIA. Since 1) is an in vitro experiment, it is not suitable for precise evaluation of the N-type Ca channel functions in living bodies. On the other hand, although 2) is an in vivo experiment, this is not suitable for precise evaluation of the N-type Ca channel functions in living bodies either because (1) selectivity of ω-conotoxin GVIA has not been completely elucidated, (2) ω-conotoxin GVIA is a peptide and hence it does not have sufficient permeability to a nerve cell, (3) a chronic-stage experiment using administration of ω-conotoxin GVIA is difficult and so forth.